15-74175441-G-A

Position:

• chr15-74175441-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005545.4(ISLR):​c.583G>A​(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ISLR NM_005545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

ISLR (HGNC:6133): (immunoglobulin superfamily containing leucine rich repeat) Predicted to be involved in cell adhesion. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11367184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISLR	NM_005545.4	c.583G>A	p.Ala195Thr	missense_variant	2/2	ENST00000249842.8
ISLR	NM_201526.2	c.583G>A	p.Ala195Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISLR	ENST00000249842.8	c.583G>A	p.Ala195Thr	missense_variant	2/2	1	NM_005545.4	P1
ISLR	ENST00000395118.1	c.583G>A	p.Ala195Thr	missense_variant	2/2	1		P1
	ENST00000561647.1	n.71+3715C>T		intron_variant, non_coding_transcript_variant		3
ISLR	ENST00000560862.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.583G>A (p.A195T) alteration is located in exon 2 (coding exon 1) of the ISLR gene. This alteration results from a G to A substitution at nucleotide position 583, causing the alanine (A) at amino acid position 195 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.082
Sift	Benign	0.14	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.015	B;B
Vest4		0.059
MutPred		0.56		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.18
MPC		0.32
ClinPred		0.18	T
GERP RS		3.1
Varity_R		0.044
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1430421838; hg19: chr15-74467782;